The proposed research will study the mechanisms by which exercise training modifies the responses of the organism to hypoxia, and the functional relevance of these modifications. Hypoxia occurs frequently in lung disease and is a feature of altitude exposure. Studies from our laboratory and others have shown that the modification of physiologic functions by exercise training could improve adaptation to hypoxia. The proposed research will study the effect of exercise training on the inflammatory response to hypoxia. Acute systemic hypoxia results in an inflammatory response characterized by increased leukocyte-endothelial interactions in the venules of several vascular beds; acclimatization leads to resolution of this lesion and to increased vascular endothelial tolerance to hypoxia. We have observed that normoxic exercise training of non-acclimatized rats prevents this inflammatory response to hypoxia. Our studies of this problem will have the following Specific Aims: the first Specific Aim will test the hypothesis that the protective effect of exercise training results from changes in the venular-endothelial balance between reactive O2 species (ROS) and nitric oxide (NO) in favor of the latter. The second Specific Aim will investigate if this protective effect, first observed in the mesentery, extends to skeletal muscle microcirculations. The third Specific Aim will evaluate the possible role of improved tissue oxygenation on the protective effect of exercise training against hypoxia. The proposed research approaches an aspect of hypoxia on which there is little information but which may have important pathophysiological implications. The studies will investigate molecular and cellular mechanisms within the physiologic context of the intact animal. Assessment of O2 transport will be complemented by determination of indices of vascular endothelial function. Several microvascular beds will be studied, including mesentery, and quiescent and contracting locomotory and non-locomotory muscles . The scope of these studies expands from our past work on systemic O2 transport to delve into the mechanisms of O2 transport and utilization at the tissue level and their interaction with vascular endothelial function.